Mirror‐Image Packing Provides a Molecular Basis for the Nanomolar Equipotency of Enantiomers of an Experimental Herbicide. (26th September 2016)

• Record Type: Journal Article
• Authors: Bisson, Claudine; Britton, K. Linda; Sedelnikova, Svetlana E.; Rodgers, H. Fiona; Eadsforth, Thomas C.; Viner, Russell C.; Hawkes, Tim R.; Baker, Patrick J.; Rice, David W.
• Is Part Of: Angewandte Chemie. Volume 128:Number 43(2016)
• Page Start: 13683
• Page End: 13687
• Publication Date: 2016-09-26
• Subjects: Chiralität -- Enantioselektivität -- Inhibitoren -- Strukturbiologie -- Wirkstoffentwicklung; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201607185
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: Programs of drug discovery generally exploit one enantiomer of a chiral compound for lead development following the principle that enantiomer recognition is central to biological specificity. However, chiral promiscuity has been identified for a number of enzyme families, which have shown that mirror‐image packing can enable opposite enantiomers to be accommodated in an enzyme's active site. Reported here is a series of crystallographic studies of complexes between an enzyme and a potent experimental herbicide whose chiral center forms an essential part of the inhibitor pharmacophore. Initial studies with a racemate at 1.85 Å resolution failed to identify the chirality of the bound inhibitor, however, by extending the resolution to 1.1 Å and by analyzing high‐resolution complexes with the enantiopure compounds, we determined that both enantiomers make equivalent pseudosymmetric interactions in the active site, thus mimicking an achiral reaction intermediate.